GABA‐producing Bifidobacterium dentium modulates visceral sensitivity in the intestine

Abstract

BackgroundRecurrent abdominal pain is a common and costly health‐care problem attributed, in part, to visceral hypersensitivity. Increasing evidence suggests that gut bacteria contribute to abdominal pain perception by modulating the microbiome‐gut‐brain axis. However, specific microbial signals remain poorly defined. γ‐aminobutyric acid (GABA) is a principal inhibitory neurotransmitter and a key regulator of abdominal and central pain perception from peripheral afferent neurons. Although gut bacteria are reported to produce GABA, it is not known whether the microbial‐derived neurotransmitter modulates abdominal pain.MethodsTo investigate the potential analgesic effects of microbial GABA, we performed daily oral administration of a specific Bifidobacterium strain (B. dentium ATCC 27678) in a rat fecal retention model of visceral hypersensitivity, and subsequently evaluated pain responses.Key ResultsWe demonstrate that commensal Bifidobacterium dentium produces GABA via enzymatic decarboxylation of glutamate by GadB. Daily oral administration of this specific Bifidobacterium (but not a gadB deficient) strain modulated sensory neuron activity in a rat fecal retention model of visceral hypersensitivity.Conclusions & InferencesThe functional significance of microbial‐derived GABA was demonstrated by gadB‐dependent desensitization of colonic afferents in a murine model of visceral hypersensitivity. Visceral pain modulation represents another potential health benefit attributed to bifidobacteria and other GABA‐producing species of the intestinal microbiome. Targeting GABAergic signals along this microbiome‐gut‐brain axis represents a new approach for the treatment of abdominal pain.

The Neuro-endocrinological Role of Microbial Glutamate and GABA Signaling

“…Recently, one Lactobacillus strain and four strains of Bifidobacterium isolated from the human intestine have been reported to being able to produce GABA (Barrett et al, 2012). Furthermore, a very recent analysis on metagenomic data from the Human Microbiome Project suggests that genes encoding GAD could be present in a significant proportion of human gut microbiota (Pokusaeva et al, 2016). Lactobacilli include the strains with the highest GABA production, although this metabolic ability is more likely strain- rather than genus-related (Li and Cao, 2010).…”

“…As far as we know, only one study concerning the modulation of host Glutamate/GABAergic systems by GABA/Glu producing gut-colonizing bacteria is available in the literature (Bravo et al, 2011). A recent study has demonstrated that a GABA-producing Bifidobacterium dentium is able to attenuate sensitivity of dorsal root ganglia neurons in a rat model of visceral pain (Pokusaeva et al, 2016). It is worth noting that these few examples refer to the limited number of studies on interaction between gut microbiota and the host nervous system which is currently available.…”

Metabiotics: The Functional Metabolic Signatures of Probiotics: Current State-of-Art and Future Research Priorities—Metabiotics: Probiotics Effector Molecules

“…and Bifidobacterium spp. improves the protein synthesis, concentration of growth hormones in the brain and regulate the lipid levels in serum [56]. Another neuroactive molecule produced by Escherichia spp.…”

The Roles of Dietary Glutamate in the Intestine

“…Moreover, both prokaryotes and eukaryotes synthesize γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter of the CNS, through the decarboxylation of Glu by glutamate decarboxylase (GAD) and genes encoding GAD are present in the gut microbiota (Lactobacillus, Bifidobacterium) than can synthesize GABA from Glu in the distal intestinal lumen. Commensal Bifidobacterium dentium produce GABA via enzymatic decarboxylation of glutamate by GadB and daily oral administration of this specific Bifidobacterium strain induced the production of GABA [21].…”